The Environmental Determinants of Diabetes in the Young (TEDDY) study was initiated in 2003 by six clinical centers in the United States and Europe, including ours, to identify infectious agents, dietary factors, or other environmental exposures that may trigger or protect against the development of islet autoimmunity and type 1 diabetes (T1D). Additional long-term scientific goals include assessment of potential gene-environment interactions affecting development of islet autoimmunity or T1D, gaining insight on mechanisms, and sharing collected specimens with broader scientific community for studies of T1D pathogenesis and prevention. A total of 424,788 newborns have been screened by HLA-DR, DQ genotyping to identify children at increased risk for T1D and 8677 are followed four times a year until 4 years of age and twice a year thereafter until age 15. Our Clinical Center has enrolled 595 TEDDY participants; of those 37 have developed persistent confirmed islet autoantibodies and 20 have been diagnosed with T1D, as of 6/30/2012. The specific aims of this renewal application for our multi-center, prospective cohort study are to: 1) Follow the TEDDY cohort of 8677 high-risk children for development of islet autoimmunity and diabetes and celiac disease for 5 more years; 2) Collect all planned biological specimens and epidemiological data according to the standard TEDDY protocol including close monitoring of performance and of the quality of samples and data; 3) Perform planned laboratory tests at appropriate times using a nested case-control study design to answer specific scientific questions and hypotheses pertinent to the TEDDY study goals; 4) Analyze and publish laboratory and epidemiological data in collaboration with the TEDDY Data Coordinating Center (funded separately), and 5) Guide the ongoing TEDDY project by participation of the Clinical Center investigators and staff in work of the study Steering Committee and sub-committees. A successful study outcome should allow better understanding of the etiology and pathogenesis of islet autoimmunity and T1D and the development of new strategies to prevent, delay, or reverse the disease.